Identification and analysis of novel regulatory mechanisms of hepatic glucose and lipid metabolism

STAT 3通过抑制肝脏中致炎基因的表达来调节葡萄糖稳态。然而，肝脏STAT 3受营养或激素状态调节的机制仍然未知。在这里，我们表明，无论是通过葡萄糖给药或静脉注射胰岛素实现的血浆胰岛素浓度的增加，刺激肝脏中的STAT 3的酪氨酸磷酸化。胰岛素的这种作用是由激素在脑中的作用介导的，并且由脑胰岛素作用诱导的肝IL-6的增加对于STAT 3的激活是必需的。在肝脏特异性STAT 3缺乏或IL-6缺乏的小鼠中，脑室内胰岛素输注诱导的肝葡萄糖产生和致炎基因表达的抑制作用受损。因此，这些结果表明，肝脏中的IL-6-STAT 3信号有助于大脑中的胰岛素作用，导致肝脏葡萄糖表达的抑制。 ...更多信息 磷酸肌醇依赖性激酶-1（PDK 1）作为磷酸肌醇3-激酶依赖性信号传导的关键介体参与胰岛素的代谢作用。在这里，我们发现，肝脏特异性PDK 1缺乏症的小鼠表现出各种缺陷的胰岛素在肝脏中的代谢作用，以及2型糖尿病样表型的特点是显着的高胰岛素血症和餐后高血糖症。在这些小鼠中，葡萄糖激酶（肝细胞中葡萄糖通量和葡萄糖诱发信号传导的重要决定因素）的肝脏丰度大幅降低。使用腺病毒载体恢复肝脏葡萄糖激酶表达，诱导肝脏中的胰岛素样作用，并使这些动物的空腹高胰岛素血症和餐后高血糖症几乎完全正常化。这些结果表明，如果维持葡萄糖激酶的肝脏丰度，即使在肝脏中近端胰岛素信号传导的急性激活（例如Akt的激活）不存在的情况下，摄入的葡萄糖也通常被处置。少

STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. The mechanism by which hepatic STAT3 is regulated by nutritional or hormonal status has remained unknown, however. Here, we show that an increase in the plasma insulin concentration, achieved either by glucose administration or by intravenous insulin infusion, stimulates tyrosine phosphorylation of STAT3 in the liver. This effect of insulin was mediated by the hormone' s effects in the brain, and the increase in hepatic IL-6 induced by the brain-insulin action is essential for the activation of STAT3. The inhibition of hepatic glucose production and of expression of gluconeogenic genes induced by intracerebral ventricular insulin infusion was impaired in mice with liver-specific STAT3 deficiency or in mice with IL-6 deficiency. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain, leading to the suppression of hepatic glucose pr … More oduction.Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver. Less